Causes and Treatment of Non-alcoholic Fatty Liver Disease (NAFLD)

Coordinators:

Michael Roden | Andreas Birkenfeld | Norbert Stefan

Members of the Academy

Andreas Birkenfeld, IDM
Triantafyllos Chavakis, PLID
Ünal Coskun, PLID
Bedair Dewidar, DDZ
Stephan Herzig, HMGU
Andrea Icks, DDZ
Wenke Jonas, DIfE
Stefan Kabisch, Charité
Sabine Kahl, DDZ
Stefan Kopf, Lübeck
Natalie Krahmer, HMGU
Eckhard Lammert, DDZ
Knut Mai, Charité
Nikolaos Perakakis, PLID
Andreas Peter, IDM
Michael Roden, DDZ
Annette Schürmann, DIfE
Norbert Stefan, IDM
Anja Zeigerer, HMGU

Metabolic dysfunction-associated steatotic liver disease (MASLD) is not only a common cause, but also a complication of prediabetes and type 2 diabetes that has been underestimated so far. DZD researchers are working on the precise treatment of (pre-)diabetes and are conducting translational studies – from experimental models to studies on humans.

Metabolic dysfunction-associated steatotic liver disease is one of the most common chronic liver diseases worldwide. In Germany, more than 18 million people are affected. Up to 75 percent of people with type 2 diabetes develop MASLD over the course of their disease, associated with an increased risk of cardiovascular events and other diabetes-related comorbidities. The Liver Academy is investigating the causes of MASLD and its inflammatory form (MASH), particularly in the context of (pre-)diabetes. The aim is to develop innovative approaches to prevention and therapy. Interdisciplinary teams work translationally on preclinical and clinical projects to test new treatment strategies and further develop existing guidelines in a targeted manner, with direct benefits for patients.

Key areas of research

  • Identification of non-invasive biomarkers and development of imaging techniques for accurate risk assessment and monitoring the progression of and response to treatment of MASLD.
  • Identification of new causes of the disease and its progression to improve precision medicine and in particular to prevent liver and diabetes-related events in MASLD.
  • Testing new treatment concepts for MASLD, especially MASH, with a focus on tailored lifestyle interventions and metabolically active drugs to develop personalized treatment approaches.

New biomarkers and imaging techniques

In collaboration with the Betacell Academy, it has been shown that certain liver hormones (hepatokines) can increase the risk of diabetes. The inhibition of the liver protein hepcidin in particular has a negative effect on the release of insulin. This research supports the development of new markers for individual risk assessment of MASLD complications. Hormonal factors also play a role: The growth factors IGF-1 and IGFBP-1 predict how well liver fat and visceral fat can be reduced through lifestyle changes. 

DZD researchers have established magnetic resonance-based methods for measuring liver energy metabolism in mouse models and in humans. In collaboration with the Academies for Prevention and Complications, procedures for the validation of liver fibrosis diagnostics have also been developed. Together with the identification of blood-based biomarkers, these new imaging techniques can help to significantly improve the diagnosis and treatment monitoring of MASLD in the future.

New treatment approaches

Successful treatment approaches for MASLD have been tested in randomized clinical studies initiated by DZD researchers. Both the optimal composition of fats and proteins in meals and the effect of metabolically active drugs (SGLT2 inhibitors with or without GLP-1 receptor agonists) were examined – with results that are important for future guidelines.

Analyses of the PLIS study have shown that a high liver fat content in high-risk cluster 5 is associated with a lack of improvement in insulin secretion. For type 2 diabetes, it has also been found that, if a lot of fat accumulates in the liver, insulin is removed from the blood more slowly. This indicates that the liver and pancreas work closely together and influence each other. 

DZD researchers were involved in the introduction of a liver health check for people with type 2 diabetes. This measure is part of a global initiative to implement personalized healthcare for diabetes.

Publications

Kupriyanova Y et al. Early changes in hepatic energy metabolism and lipid content in recent-onset type 1 and 2 diabetes mellitus. J Hepatol (2021). https://doi.org/10.1016/j.jhep.2020.11.030

Sekar R et al. Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes. Cell Metab (2022). https://doi.org/10.1016/j.cmet.2022.10.013

Stefan N et al. The Role of hepatokines in NAFLD. Cell Metab (2023). https://doi.org/10.1016/j.cmet.2023.01.006

Kahl S et al. Dysglycemia and liver lipid content determine the relationship of insulin resistance with hepatic OXPHOS capacity in obesity. J Hepatol (2024). https://doi.org/10.1016/j.jhep.2024.08.012

Sanyal A et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis. NEJM (2025). https://doi.org/10.1056/NEJMoa2413258